This application details a comprehensive five-year training program for mentored career development in patient-oriented research. The applicant completed clinical training in internal medicine at the Brigham and Women's Hospital and endocrinology at the Massachusetts General Hospital (MGH). Concurrent with his clinical training, he earned a Masters in Clinical and Translational Science from Harvard Medical School, conducted genetic research in type 2 diabetes (T2D) development, and applied metabolite profiling to study medication-induced changes in individuals at risk of T2D. He proposes a research program specifically constructed to provide focused training in translational metabolomics, genetic, and clinical intervention approaches that will serve as the foundation for his transition towards an independent career as a physician-scientist. The applicant aims to combine his prior training in clinical medicine, human physiology, metabolomics, and genetics with newly acquired skills within a structured environment to accomplish this goal. He has chosen mentors with complementary expertise: Dr. Jose Florez is an expert in human genetics and pharmacogenetics with a strong background in human physiology research, and he is Chair of the Diabetes Prevention Program Genetics Working Group; and Dr. Robert Gerszten is co-PI of the Metabolite Profiling Platform at the Broad Institute and Director of Translational Research at the MGH Heart Center. Both investigators have a strong record of mentorship with trainees progressing to scientific independence. The applicant's career development plan entails rigorous coursework and seminars, hands-on practical experience, and close guidance from a network of scientific advisors with diverse scientific expertise yet uniform commitment to the career development of the applicant. The scientific aims of this application are to: 1. derive the pharmacometabolite signature of acute and chronic metformin response; 2) integrate genetics and metabolomics to characterize metabolic factors of metformin response; and 3) modulate the pharmacometabolite signature of metformin response through clinical intervention. To accomplish these aims, the applicant will utilize state-of-art metabolomic and genomic platforms at the Broad Institute to assess metabolite levels and associated genetic loci in the Diabetes Prevention Program (DPP), a completed clinical trial that identified metformin as an effective strategy for T2D prevention, and the Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans, a novel pharmacogenetic and metabolomics resource, which he has helped develop over the past 5 years. These aims will identify metabolic factors that influence metformin response, characteristics of individuals who are most likely to benefit from this preventive intervention, and targets for novel T2D prevention strategies. Collectively, the experience gained during this award will serve as the foundation for the applicant's independent, academic career as a physician-scientist with expertise in translational research in human metabolic disease and a mission of improving strategies for T2D prevention and treatment.